Hyperosmotic blood-brain barrier disruption in brains of rats with an intracerebrally transplanted RG-C6 tumor

1987 ◽  
Vol 66 (2) ◽  
pp. 256-263 ◽  
Author(s):  
Tooru Inoue ◽  
Masashi Fukui ◽  
Shunji Nishio ◽  
Katsutoshi Kitamura ◽  
Hitoshi Nagara
Keyword(s):  
Blood Brain Barrier ◽  
Brain Regions ◽  
Progressive Increase ◽  
Brain Barrier ◽  
Blue Dye ◽  
Normal Brain ◽  
Content Type ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Bbb Opening

✓ To test the results of blood-brain barrier (BBB) disruption in the treatment of brain tumor, RG-C6 glioma was transplanted into the brains of rats. Intracarotid infusions of normal saline and hyperosmotic mannitol were then made, followed by intravenous injection of Evans blue dye plus albumin (EB, MW 68,000), horseradish peroxidase (HRP, MW 40,000), and 5-fluorouracil (5-FU, MW 130). Uptake of the drug and the consistency of drug levels in the normal brain and tumor varied widely among these three agents. Both EB and HRP penetrated the brain tumors but did not stain the normal brain tissues. After BBB opening, penetration of EB and HRP into the normal brain was drastically increased; however, the uptake of EB and HRP in the tumor was not increased. The concentration of 5-FU in the tumor was higher than that in the serum and, although it increased 1.5-fold after BBB opening, the increase was not statistically significant. Conversely, there was a progressive increase in concentrations of 5-FU in the tumor-free brain regions (p < 0.05). These observations suggest that an intracarotid infusion of hyperosmotic mannitol may increase neurotoxicity because it allows greater delivery of anticancer drugs into the normal brain tissue than into the tumor tissues.

Quantification and pharmacokinetics of blood-brain barrier disruption in humans

1996 ◽  
Vol 85 (6) ◽  
pp. 1056-1065 ◽  
Author(s):  
Bernhard Zünkeler ◽  
Richard E. Carson ◽  
Jeff Olson ◽  
Ronald G. Blasberg ◽  
Hetty Devroom ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Normal Brain ◽  
Content Type ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
Fine Print

✓ Hyperosmolar blood-brain barrier disruption (HBBBD), produced by infusion of mannitol into the cerebral arteries, has been used in the treatment of brain tumors to increase drug delivery to tumor and adjacent brain. However, the efficacy of HBBBD in brain tumor therapy has been controversial. The goal of this study was to measure changes in vascular permeability after HBBBD in patients with malignant brain tumors. The permeability (K1) of tumor and normal brain blood vessels was measured using rubidium-82 and positron emission tomography before and repeatedly at 8- to 15-minute intervals after HBBBD. Eighteen studies were performed in 13 patients, eight with glioblastoma multiforme and five with anaplastic astrocytoma. The HBBBD increased K1 in all patients. Baseline K1 values were 2.1 ± 1.4 and 34.1 ± 22.1 µl/minute/ml (± standard deviation) for brain and tumor, respectively. The peak absolute increases in K1 following HBBBD were 20.8 ± 11.7 and 19.7 ± 10.7 µl/minute/ml for brain and tumor, corresponding to percentage increases of approximately 1000% in brain and approximately 60% in tumor. The halftimes for return of K1 to near baseline for brain and tumor were 8.1 ± 3.8 and 4.2 ± 1.2 minutes, respectively. Simulations of the effects of HBBBD made using a very simple model with intraarterial methotrexate, which is exemplary of drugs with low permeability, indicate that 1) total exposure of the brain and tumor to methotrexate, as measured by the methotrexate concentration-time integral (or area under the curve), would increase with decreasing infusion duration and would be enhanced by 130% to 200% and by 7% to 16%, respectively, compared to intraarterial infusion of methotrexate alone; and 2) exposure time at concentrations above 1 µM, the minimal concentration required for the effects of methotrexate, would not be enhanced in tumor and would be enhanced by only 10% in brain. Hyperosmolar blood-brain barrier disruption transiently increases delivery of water-soluble compounds to normal brain and brain tumors. Most of the enhancement of exposure results from trapping the drug within the blood-brain barrier, an effect of the very transient alteration of the blood-brain barrier by HBBBD. Delivery is most effective when a drug is administered within 5 to 10 minutes after disruption. However, the increased exposure and exposure time that occur with methotrexate, the permeability of which is among the lowest of the agents currently used clinically, are limited and the disproportionate increase in brain exposure, compared to tumor exposure, may alter the therapeutic index of many drugs.

The effect of steroids on gentamicin delivery to brain after blood-brain barrier disruption

1990 ◽  
Vol 72 (1) ◽  
pp. 123-126 ◽  
Author(s):  
Edward A. Neuwelt ◽  
Alfred Horaczek ◽  
Michael A. Pagel
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Structural Damage ◽  
Vasogenic Edema ◽  
Brain Barrier ◽  
Normal Brain ◽  
Content Type ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Wide Range

✓ Osmotic modification of the blood-brain barrier (BBB) provides an experimental model of vasogenic edema, is totally reversible, and does not cause any structural damage. In the present communication, the effect of corticosteroids on drug delivery to normal rat brain was evaluated in this model. Intraperitoneal dexamethasone was administered at doses ranging from 12 to 48 mg/sq m for 3 days; gentamicin delivery to the brain was then evaluated after either intravenous or intracarotid administration in both control and BBB-modified animals. Only animals receiving the highest dose of dexamethasone and in which the gentamicin was given intravenously demonstrated a statistically significant decrease in drug delivery. The effect of dexamethasone over a wide range of dosages, therefore, exhibited only modest effects on drug delivery to normal brain after osmotic BBB disruption.

Selective blood-tumor barrier disruption by leukotrienes

1992 ◽  
Vol 77 (3) ◽  
pp. 407-410 ◽  
Author(s):  
Chung-Ching Chio ◽  
Takehiko Baba ◽  
Keith L. Black
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Normal Brain ◽  
Barrier Permeability ◽  
Content Type ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
The Mean ◽  
Fine Print

✓ The authors have previously reported that intracarotid infusion of 5 µg leukotriene C4 (LTC4) selectively increases blood-tumor barrier permeability in rat RG-2 tumors. In this study, rats harboring RG-2 tumors were given 15-minute intracarotid infusions of LTC4 at concentrations ranging from 0.5 µg to 50.0 µg (seven rats in each dose group). Blood-tumor and blood-brain barrier permeability were determined by quantitative autoradiography using 14C aminoisobutyric acid. The transfer constant for permeability (Ki) within the tumors was increased twofold by LTC4 doses of 2.5, 5.0, and 50.0 µg compared to vehicle alone (90.00 ±21.14, 92.68 ± 15.04, and 80.17 ± 16.15 vs. 39.37 ± 6.45 µl/gm/min, respectively; mean ± standard deviation; p < 0.01). No significant change in Ki within the tumors was observed at the 0.5-µg LTC4 dose. Blood-brain barrier permeability was selectively increased within the tumors. At no dose in this study did leukotrienes increase permeability within normal brain. To determine the duration of increased opening of the blood-tumor barrier by LTC4 administration, Ki was measured at 15, 30, and 60 minutes after termination of a 15-minute LTC4 infusion (seven rats at each time point). The mean Ki value was still high at 15 minutes (92.68 ± 15.04 µl/gm/min), but declined at 30 minutes (56.58 ± 12.50 µl/gm/min) and 60 minutes (55.40 ± 8.10 µl/gm/min) after the end of LTC4 infusion. Sulfidopeptide leukotrienes LTC4, LTD4, LTE4 and LTF4 were infused to compare their potency in opening the blood-tumor barrier. The mean leukotriene E4 was the most potent, increasing the permeability value 37½ fold compared with vehicle alone (139.86 ± 23.95 vs. 39.37 ± 6.45 µl/gm/min).

The effect of interleukin-2 on the blood-brain barrier in the 9L gliosarcoma rat model

1989 ◽  
Vol 70 (1) ◽  
pp. 92-96 ◽  
Author(s):  
Joseph T. Alexander ◽  
Stephen C. Saris ◽  
Edward H. Oldfield
Keyword(s):  
Blood Brain Barrier ◽  
Interleukin 2 ◽  
Brain Barrier ◽  
High Dose ◽  
Normal Brain ◽  
Content Type ◽  
Tumor Bearing ◽  
Blood Brain ◽  
Significant Difference ◽  
Fine Print

✓ Carbon-14-labeled aminoisobutyric acid was used to determine local blood-to-tissue transfer constants in 22 Fischer rats with intracerebral 9L gliosarcomas that received either high-dose parenteral interleukin-2 (IL-2) or a control injection. In tumor and peritumoral tissue, the transfer constants in the IL-2-treated animals (89.6 ± 14.6 and 35.8 ± 6.0, respectively, mean ± standard error of the mean) were larger (p < 0.05) than in control animals (61.4 ± 6.4 and 14.6 ± 2.2, respectively). In contrast, in normal frontal and occipital tissue contralateral to the tumor-bearing hemisphere, there was no significant difference between the transfer constants in IL-2-treated and control animals. Furthermore, treatment of animals with IL-2 excipient caused no change in permeability as compared to animals treated with Hanks' balanced salt solution. Parenteral injection of IL-2 increases blood-brain barrier disruption in tumor-bearing rat brain but does not increase the vascular permeability of normal brain. Methods to prevent this increased tumor vessel permeability are required before parenteral IL-2 can be used safely for the treatment of primary or metastatic brain tumors.

Comparison of the Effect of the Carbon Dioxide Laser and the Bipolar Coagulator on the Cat Brain

Neurosurgery ◽  
1985 ◽  
Vol 16 (4) ◽  
pp. 449-453 ◽  
Author(s):  
Jeffrey W. Cozzens ◽  
Leonard J. Cerullo
Keyword(s):  
Carbon Dioxide ◽  
Blood Brain Barrier ◽  
Carbon Dioxide Laser ◽  
Surgical Instruments ◽  
Brain Barrier ◽  
Blue Dye ◽  
Physiological Level ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption

Abstract The carbon dioxide laser has recently received clinical acceptance in neurosurgical practice. There are, however, few studies reported in the neurosurgical literature, either clinical or experimental, concerning its safety or efficacy on a physiological level by comparison to a more conventional tool. This study is not a description of a surgical technique, but is rather a basic physiological comparison of two surgical instruments. In this study, 11 cats were pretreated with the protein-bound dye, Evans blue. A corticotomy was performed in one hemisphere with the carbon dioxide laser and in the other with a microbipolar coagulator and a sharp blade. The subsequent extravasation of dye was presumed to be proportional to the amount of blood-brain barrier disruption associated with each lesion. When effective power settings for the two devices were compared, the laser lesions had significantly less extravasation of blue dye. This indicated that there was less damage to the blood-brain barrier surrounding laser corticotomy than surrounding conventional bipolar coagulation and sharp dissection at comparable power settings for each modality.

Cerebrovascular permeability and delivery of gentamicin to normal brain and experimental brain abscess in rats

1984 ◽  
Vol 61 (3) ◽  
pp. 430-439 ◽  
Author(s):  
Edward A. Neuwelt ◽  
David E. Baker ◽  
Michael A. Pagel ◽  
Nathan K. Blank
Keyword(s):  
Brain Abscess ◽  
Blood Brain Barrier ◽  
Medical Management ◽  
Brain Barrier ◽  
High Dose ◽  
Normal Brain ◽  
Content Type ◽  
Stage Of Development ◽  
Blood Brain ◽  
Brain Abscesses

✓ Antibiotics vary widely in their ability to penetrate the blood-brain barrier. In studies of 70 rats, the permeability of the normal blood-brain barrier to gentamicin was shown to be poor. In experimental brain abscesses, during the cerebritic stage of development, the penetration of intravenous antibiotics was increased compared to normal brain but was very inconsistent. Antibiotic delivery to brain abscess was not significantly altered with the administration of high-dose steroids, but the macrophage and glial response was markedly decreased with high-dose steroid therapy. Reversible osmotic blood-brain barrier modification with mannitol increased the delivery of gentamicin both to brain abscess and to the surrounding brain. It also resulted in more consistent tissue drug levels. The clinical implications of these studies suggest that, because of the inconsistent delivery of gentamicin to brain abscess, the therapeutic efficacy of medical management alone may be quite variable. This mode of therapy could possibly increase the efficacy of medical management of brain abscesses, especially in patients with multiple or surgically inaccessible brain abscesses.

Blood-brain barrier disruption in immature Fischer 344 rats

1984 ◽  
Vol 60 (4) ◽  
pp. 743-750 ◽  
Author(s):  
Dennis E. Bullard ◽  
Darell D. Bigner
Keyword(s):  
Blood Brain Barrier ◽  
Small Animal ◽  
Chemotherapeutic Agents ◽  
Brain Barrier ◽  
External Carotid ◽  
Blue Dye ◽  
Fischer 344 Rats ◽  
Content Type ◽  
Fischer 344 ◽  
Blood Brain

✓ Methods for transiently disrupting the blood-brain barrier (BBB) which are consistent with survival are described for immature Fischer 344 rats weighing 40 to 99 gm. A catheter was retrogradely inserted into the external carotid artery to the level of the bifurcation. Perfusion of 1.4 M mannitol or 1.6 M arabinose, at a rate of 0.01 to 0.1 ml/sec for 30 seconds, resulted in transient BBB disruption as measured by Evans blue dye (EBD) staining. Higher flow rates or perfusion with 10% to 30% dimethyl sulfoxide were associated with a mortality rate ranging from 0% to 44%. Perfusion with 0.9% sodium chloride or intrafemoral artery perfusion with 1.4 M mannitol did not disrupt the BBB. Optimum BBB disruption as measured by EBD staining was achieved with 1.6 M arabinose at 0.026 ml/sec for 30 seconds, at which time all of the 42 experimental animals had BBB disruption; all of the animals so treated survived 2 weeks following perfusion. This technique will allow the efficacy of delivering chemotherapeutic agents following BBB disruption to be tested in several of the more commonly used small-animal models for brain-tumor research.

Etoposide-induced blood-brain barrier disruption

1984 ◽  
Vol 61 (4) ◽  
pp. 674-678 ◽  
Author(s):  
Melvin K. Spigelman ◽  
Rosario A. Zappulla ◽  
James Johnson ◽  
Stanley J. Goldsmith ◽  
Leonard I. Malis ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Tween 80 ◽  
Brain Barrier ◽  
Control Group ◽  
Sprague Dawley ◽  
Content Type ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Sprague Dawley Rats ◽  
Brain Barrier Disruption

✓ The intracarotid infusion of the anti-neoplastic compound, etoposide, has been shown to exert a dose-dependent effect on blood-brain barrier (BBB) permeability. Etoposide, however, is formulated in a complex solvent solution containing alcohol, Tween 80, polyethylene glycol 300, and citric acid. To investigate the contribution of the solvent solution to BBB disruption, the authors studied Sprague-Dawley rats after the internal carotid artery infusion of the solvent solution with and without the addition of etoposide. Experiments were performed at four doses of drug and/or solvent. Disruption of the BBB was evaluated qualitatively by the appearance of the systemically administered dye, Evans blue, in the cerebral hemispheres and quantitatively by the ratio of gamma counts of the technetium-labeled chelate of diethylenetriaminepentaacetic acid (99mTc-DTPA) in the ipsilateral:contralateral hemisphere. Significant barrier opening was obtained in all four groups of animals infused with solvent plus etoposide. In the corresponding groups of rats infused with the solvent solution alone, BBB disruption was markedly lower. Only in the group infused with the largest dose of solvent was the hemispheric ratio of 99mTc-DTPA significantly different from saline-infused animals. Each of the groups with solvent plus etoposide had 99mTc-DTPA ratios significantly different from the control group. Intracarotid infusion and subsequent BBB disruption were well tolerated by the animals receiving either solvent alone or solvent and etoposide. Disruption of the BBB secondary to the intracarotid infusion of etoposide is primarily caused by the drug itself and not by the solvent solution.

scholarly journals Blood–Brain Barrier Modulation to Improve Glioma Drug Delivery

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1085
Author(s):  
Huilong Luo ◽  
Eric V. Shusta
Keyword(s):  
Blood Brain Barrier ◽  
Clinical Success ◽  
Brain Barrier ◽  
Microvascular Endothelial Cells ◽  
Normal Brain ◽  
Normal Brain Tissue ◽  
The Poor ◽  
Blood Brain ◽  
Significant Obstacle ◽  
Bbb Opening

The blood–brain barrier (BBB) is formed by brain microvascular endothelial cells that are sealed by tight junctions, making it a significant obstacle for most brain therapeutics. The poor BBB penetration of newly developed therapeutics has therefore played a major role in limiting their clinical success. A particularly challenging therapeutic target is glioma, which is the most frequently occurring malignant brain tumor. Thus, to enhance therapeutic uptake in tumors, researchers have been developing strategies to modulate BBB permeability. However, most conventional BBB opening strategies are difficult to apply in the clinical setting due to their broad, non-specific modulation of the BBB, which can result in damage to normal brain tissue. In this review, we have summarized strategies that could potentially be used to selectively and efficiently modulate the tumor BBB for more effective glioma treatment.

Brain damage from 125I brachytherapy evaluated by MR imaging, a blood-brain barrier tracer, and light and electron microscopy in a rat model

1990 ◽  
Vol 73 (4) ◽  
pp. 585-593 ◽  
Author(s):  
Mark Bernstein ◽  
Tom Marotta ◽  
Patricia Stewart ◽  
Jennifer Glen ◽  
Lothar Resch ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Mr Imaging ◽  
Blood Brain Barrier ◽  
Light And Electron Microscopy ◽  
Brain Barrier ◽  
Content Type ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Normal Rat ◽  
Brain Barrier Disruption

✓ Changes in normal rat brain were studied acutely, and at 3, 6, 9, and 12 months following interstitial brachytherapy with high-activity 125I seeds. An 80-Gy radiation dose was administered to an area with a 5.5-mm radius. Effects were measured with magnetic resonance (MR) imaging (with and without gadolinium enhancement), leakage of horseradish peroxidase(HRP), electron microscopy, and light microscopy. Significant histological damage was seen at radiation doses above 295 Gy, and breakdown of the blood-brain barrier was observed only in tissue receiving a dose of 165 Gy or greater. Blood-brain barrier breakdown increased up to the 6-month time point, and thereafter appeared to stabilize or decrease. The area of blood-brain barrier disruption indicated by gadolinium-enhanced MR imaging was greater than that indicated by leakage of HRP.

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